A 6-month, multicenter, open-label study of fixed dose naproxen/esomeprazole in adolescent patients with juvenile idiopathic arthritis

Abstract

Background: Juvenile idiopathic arthritis (JIA) is an inflammatory arthritis of unknown etiology, which lasts for greater than 6 weeks with onset before 16 years of age. JIA is the most common chronic rheumatic disease in children. NSAIDs have been the mainstay of initial management with naproxen (NAP) being commonly used, but they may cause serious side effects such as gastric ulcers which can be reduced by concomitant administration of proton pump inhibitors, such as esomeprazole (ESO).

Methods: Primary objective was to evaluate the safety and tolerability of 3 fixed doses of NAP/ESO in JIA patients aged 12 to 16 years. Forty-six children and adolescents with JIA by International League of Associations for Rheumatology criteria, mean age of 13.6 years, from 18 US sites were prospectively enrolled over 2 years and followed for up to 6 months. Doses of the NAP/ESO fixed combination were based on baseline weight. The exploratory efficacy outcome was assessed with the ACR Pediatric-30, - 50, - 70, - 90 Response and the Childhood Health Assessment Questionnaire (CHAQ) discomfort and functional scores at months 1, 3, and 6 as change from baseline. Occurrence and causality were assessed for treatment emergent AEs (TEAEs) and discontinuations were monitored monthly.

Results: Forty-six patients received at least 1 dose of naproxen/esomeprazole and 36 completed the trial. Thirty-seven (80.4%) had at least 1 treatment emergent adverse event (TEAE) and, with the exception of 2 events in one patient, all of the TEAEs were mild or moderate. Frequent TEAEs (≥5% of patients) were upper respiratory tract and gastrointestinal related. Eleven (23.9%) had at least 1 TEAE considered to be related to study drug. Four patients (8.7%) discontinued due to a TEAE with one of these being the only serious AE reported, acute hepatitis. Mean number of active joints at baseline was 3.1. Improvement in JIA signs and symptoms occurred at most assessments and by month 6, the percentage of patients with an ACR Pediatric-30, - 50, - 70, and - 90 Response was 47.1, 38.2, 32.4, and 17.6%, respectively. The percent of patients achieving ACR Pediatric response increased over time. CHAQ discomfort improved at each assessment and functional scores improved at all assessments for 'Arising, Walking, and Activities' with several improved for 'Dressing and Grooming, Eating, Hygiene, and Grip'. There was no indication of a dose-related efficacy effect.

Conclusion: NAP/ESO was well tolerated in JIA patients aged 12 to 16 years with high levels of response to ACR criteria. No new safety signals were identified for the well-characterized components of this fixed dosed JIA treatment, which was developed to reduce the risk of gastric ulcers.

Trial registration: Clinicaltrials.gov, NCT01544114 . Registered February 21, 2012.

Keywords: Esomeprazole; Juvenile idiopathic arthritis; Naproxen; Non-steroidal anti-inflammatory drugs (NSAIDs).

Conflict of interest statement

Ethics approval and consent to participate

An Institutional Review Board (IRB)/Ethics Committee (EC) from each clinical study site approved the final study protocol, and the final version of the informed consent form and assent form and any other written information and/or materials provided to the patients before any patients were entered in the study. Before being implemented, protocol amendments were reviewed and approved by the IRBs.

Consent for publication

Not applicable.

Competing interests

D.J.L. receives grant / research support from the National Institutes of Health, NIAMS; Cincinnati Children’s Hospital Medical Center receives funds for DJL consulting from AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, and Janssen for consulting; He is on the speaker bureaus of Genentech and Bristol Meyers Squibb. J.A.D. has received research support from AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche and UCB. D.G. is on Novartis speaker bureau. L.J. has received research support from Abbvie, GSk, Hoffman-Laroche, Pfizer and UCB. A.Z. has stock ownership in Merck and OPKO. J.B., B.D.L., M. F. and R.J. H. are employees of, and have stock in, Horizon Pharma USA, Inc.

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Figures

Fig. 1

Overview of Study Design. Visits 1 and 2 could have been combined if results from all assessments at Visit 1 were obtained at the time of Visit 1. If Visits 1 and 2 were conducted on the same day, visit procedures that were specific to Visit 2 were also conducted during Visit 1. The telephone call during the 2-week safety follow-up period was required for all patients (i.e., patients who completed the full 6 months of treatment, patients who completed less than 6 months of treatment, patients who discontinued early from the study, and patients who took at least 1 dose of study drug)

Fig. 2

ACR Scores. The number above each bar represents the number of patients at that dose. The four patients in the lowest dose group did not reach any ACR response at Month 1. The ACR Pediatric-30, −50, −70, and − 90 responses were defined as an improvement of at least 30% (or 50, 70, 90%, respectively) from baseline in at least 3 of the 6 signs and symptoms variables, with no more than 1 of the remaining variables worsening by > 30%. JIA signs and symptoms variables: physician’s global assessment of disease activity, CHAQ disability index score, CHAQ global assessment of well-being, number of joints with active arthritis, number of joints with limited range of motion, serum CRP or ESR

Fig. 3

ACR Response in patients with co-therapy and in patients with NSAID as primary therapy at month 6